Fumaric acid esters have been used for the treatment of moderate to severe psoriasis. In 1994, mixture of fumaric acid esters like dimethyl fumarate ester and monoethyl fumarate was approved in Germany, for the treatment of psoriasis. The product was marketed under the tradename Fumaderm®. (Ruggieri et al, Therapeutics and Clinical Risk management, 2014, 10, 229-239). Fumaderm® is an enteric coated tablet comprising dimethyl fumarate, monoethylfumarate fumarate Ca-salt, monoethylfumarate fumarate Mg-salt and monoethylfumarate Zn-salt.
Fumaric acid and its derivatives like dimethyl fumarates was known to cause local irritation of the intestinal mucous membrane when administered as conventional tablet, as the ingredients of the tablet were released in the intestine at a concentration which was too high. These side effects were evident with Fumaderm , which due to high concentration of drug release in the stomach, was known to cause undesirable side effects like nausea, vomiting, abdominal cramps, headache, dizziness and flushing (Antonie et al, Indian Journal of Dermatology, Venereology and Leprology, Vol. 73, No. 2, March-April, 2007, pp. 133-137)
An improved capsule formulation of dimethyl fumarate was approved by USFDA in 2013, under the tradename Tecfidera® (Biogen Idec, Inc) for the treatment of multiple sclerosis. Tecfidera® comprises enteric-coated micro-tablets in capsules, wherein it is theorized that the micro-tablets are incrementally released by the stomach and passed into the small intestine and the active ingredients are released in smaller dosages, thus avoiding the gastrointestinal irritations and side effects. (See U.S. Pat. No. 7,320,999). Tecfidera® is used in Multiple sclerosis patients at a starting dose of 120 mg twice a day. After 7 days, the dose is increased to the maintenance dose of 240 mg twice a day. The product, however, has also been reported to cause the adverse events associated with flushing and gastrointestinal side effects such as diarrhea, abdominal pain, nausea, flatulence etc. (Phillips et al., Multiple Sclerosis and Related Disorders (2014) 3, 513-519). It is further known to show high variability in pharmacokinetic profiles (Sheikh et al., Clinical Therapeutics, 2013, Vol. 35, NO. 10, 1583-1594). Another approach for reducing the side effects associated with dimethyl fumarate, contemplated in the art is through use of controlled release formulations as disclosed in US20090304790 and WO2015028472.
Orally administered dimethyl fumarate is prone to presystemic metabolism by esterases associated with the intestinal lumen and the mucosa which is responsible for the rapid disappearance of the drug from the absorption site. The approved label of Tecfidera® suggests rapid presystemic hydrolysis of dimethyl fumarate to its active metabolite, monomethyl fumarate (MMF) and that dimethyl fumarate is not quantifiable in plasma. Werdenberg et al. also discloses complete biotransformation of dimethyl fumarate to MMF, before reaching the liver (Werdenberg et al., Biopharm. Drug Dispos. 2003, 24: 259-273).
The present invention is a novel improved pharmaceutical composition of dimethyl fumarate which addresses these drawbacks. Unlike the prior art approach of making a controlled release formulation, the present inventors have formulated a delayed release composition which exhibits increased bioavailability as compared to Tecfidera® when administered at same dose under similar conditions. The term “increased bioavailability” is intended to mean that the composition of the present invention requires a lower dose to equivalent blood levels of the active metabolite, monomethyl fumarate compared to that of Tecfidera® capsules. Further the term “dose” refers to the amount of dimethyl fumarate in the composition in the form of a capsule. The capsules are given twice daily and therefore the “daily dose” is the amount of dimethyl fumarate in two capsules.